Meta-Analysis Open Access
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Dec 15, 2023; 15(12): 2225-2236
Published online Dec 15, 2023. doi: 10.4251/wjgo.v15.i12.2225
Association of MBOAT7 rs641738 polymorphism with hepatocellular carcinoma susceptibility: A systematic review and meta-analysis
Min Lai, Qiong-Yu Jin, Wen-Jing Chen, Jia Hu, Department of Gastroenterology, the Third Affiliated Hospital of Chengdu Medical College/Chengdu Pidu District People's Hospital, Chengdu 611730, Sichuan Province, China
Ya-Lu Qin, Department of Cardiology, the Affiliated Third Hospital of Chengdu Traditional Chinese Medicine University/Chengdu Pidu District Hospital of Traditional Chinese Medicine, Chengdu 611730, Sichuan Province, China
ORCID number: Min Lai (0009-0009-8712-0980).
Co-first authors: Min Lai and Ya-Lu Qin.
Author contributions: Lai M and Qin YL conceived, designed, and refined the study protocol; Lai M, Qin YL, Jin QY, Chen WJ, and Hu J were involved in the data collection; Lai M, Qin YL, and Jin QY analyzed the data; Lai M and Qin YL drafted the manuscript; all authors were involved in the critical review of the results and have contributed to, read, and approved the final manuscript. Lai M and Qin YL contributed equally to this work as co-first authors. The reasons for designating Lai M and Qin YL as co-first authors are threefold. First, the research was performed as a collaborative effort, and the designation of co-first authorship accurately reflects the distribution of responsibilities and burdens associated with the time and effort required to complete the study and the resultant paper. This also ensures effective communication and management of post-submission matters, ultimately enhancing the paper's quality and reliability. Second, the overall research team encompassed authors with a variety of expertise and skills from different fields, and the designation of co-first authors best reflects this diversity. This also promotes the most comprehensive and in-depth examination of the research topic, ultimately enriching readers' understanding by offering various expert perspectives. Third, Lai M and Qin YL contributed efforts of equal substance throughout the research process. The choice of these researchers as co-first authors acknowledges and respects this equal contribution, while recognizing the spirit of teamwork and collaboration of this study. In summary, we believe that designating Lai M and Qin YL as co-first authors is fitting for our manuscript as it accurately reflects our team's collaborative spirit, equal contributions, and diversity.
Conflict-of-interest statement: The authors have nothing to disclose.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2020 Checklist, and the manuscript was prepared and revised according to the PRISMA 2020 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Min Lai, MD, Doctor, Department of Gastroenterology, the Third Affiliated Hospital of Chengdu Medical College/Chengdu Pidu District People's Hospital, No. 666 Section 2, Deyuan North Road, Pidu District, Chengdu 611730, Sichuan Province, China. laimin1128Lm@126.com
Received: August 27, 2023
Peer-review started: August 27, 2023
First decision: October 18, 2023
Revised: October 23, 2023
Accepted: November 17, 2023
Article in press: November 17, 2023
Published online: December 15, 2023
Processing time: 108 Days and 21.5 Hours

Abstract
BACKGROUND

The MBOAT7 rs641738 single-nucleotide polymorphism (SNP) has been proven to influence various liver diseases, but its association with hepatocellular carcinoma (HCC) susceptibility has been debated. To address this discrepancy, we conducted the current systematic review and meta-analysis.

AIM

To perform a systematic review and meta-analysis on association of MBOAT7 SNP and HCC susceptibility.

METHODS

We performed a systematic review in PubMed, Web of Science, Scopus, and EMBASE; applied specific inclusion and exclusion criteria; and extracted the data. Meta-analysis was conducted with the meta package in R. Sensitivity and subgroup analyses were also performed. This meta-analysis was registered in PROSPERO (CRD42023458046).

RESULTS

Eight studies were included in the systematic review, and 12 cohorts from 6 studies were included in the meta-analysis. Our meta-analysis revealed an association between the MBOAT7 SNP and HCC susceptibility in both the dominant [odds ratio (OR): 1.14, 95% confidence interval (95%CI): 1.02-1.26, P = 0.020] and recessive (OR: 1.21, 95%CI: 1.05-1.39, P = 0.008) models. Subgroup analysis revealed that stratification of the included patients by geographical origin showed a significant association in Asia (OR: 1.20, 95%CI: 1.03-1.39).

CONCLUSION

This meta-analysis underscores the contribution of the MBOAT7 rs641738 SNP to hepatocarcinogenesis, especially in Asian populations, which warrants further investigation.

Key Words: MBOAT7; Single-nucleotide polymorphisms; Hepatocellular carcinoma; Systematic review; Meta-analysis; Asian populations

Core Tip: We conducted the current systematic review and meta-analysis to address the association between MBOAT7 rs641738 SNP and HCC susceptibility. We demonstrated the correlation between MBOAT7 rs641738 SNP and HCC susceptibility both in the dominant and recessive models, and subgroup analysis revealed the significant association especially in Asia populations, which could guide clinical practice in the identification of at-risk population.
INTRODUCTION

Hepatocellular carcinoma (HCC), which ranks as the fourth leading cause of cancer-related mortality worldwide, presents a substantial challenge in the health care landscape[1]. Over 80% of HCC cases occur in low-resource and middle-resource countries, particularly in eastern Asia, where medical and social care resources are often constrained[2,3]. To address this challenge, early detection, improved management, and careful monitoring of high-risk populations are essential strategies.

Germline DNA single-nucleotide polymorphisms (SNPs) likely represent etiology-specific host factors that determine HCC susceptibility, including SNPs within PNPLA3 (patatin like phospholipase domain containing 3), TM6SF2 (transmembrane 6 superfamily 2), and MBOAT7 (membrane-bound O-acyltransferase domain-containing 7)[4]. The association between the PNPLA3 rs738409 SNP and HCC has already been demonstrated by Singal et al[5], who indicated that PNPLA3 is an independent risk factor for HCC. Furthermore, the association between the TM6SF2 rs58542926 SNP and HCC has been illustrated by Tang et al[6], who also suggested a significant association of the TM6SF2 SNP with HCC risk.

Interestingly, another previously studied SNP is the missense rs641738 C > T variant positioned downstream of the MBOAT7 locus. The MBOAT7 rs641738 SNP has been proven to influence histological liver damage in alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), hepatitis C, and hepatitis B[7]. However, its association with HCC has been debated. Thabet et al[8] performed a large case-control study in patients with hepatitis C virus (HCV)-related HCC and found that the role of rs641738 is limited to the early stages of liver disease but not to further progression or occurrence of HCC. Conversely, Donati et al[9] found that the MBOAT7 rs641738 T allele may predispose patients without cirrhosis to HCC.

To address this discrepancy, we conducted the current systematic review and meta-analysis on the association of the MBOAT7 SNP and HCC susceptibility, aiming to provide an updated and comprehensive assessment of the evolving evidence in this area.

MATERIALS AND METHODS
Search strategy

We performed a systematic review using the following search strategy in four different databases (PubMed, Web of Science, Scopus, and EMBASE, searched in August 2023): (1): Neoplasms, Hepatic OR Neoplasms, Liver OR Liver Neoplasm OR Neoplasm, Liver OR Hepatic Neoplasms OR Hepatic Neoplasm OR Neoplasm, Hepatic OR Cancer of Liver OR Hepatocellular Cancer OR Cancers, Hepatocellular OR Hepatocellular Cancers OR Hepatic Cancer OR Cancer, Hepatic OR Cancers, Hepatic OR Hepatic Cancers OR Liver Cancer OR Cancer, Liver OR Cancers, Liver OR Liver Cancers OR Cancer of the Liver OR Cancer, Hepatocellular; (2): Membrane bound O-acyltransferase domain-containing 7 protein, human OR MBOAT7 protein, human OR MBOAT7 OR membrane bound O-acyltransferase domain-containing 7; and (3): (1) AND (2).

Study selection

The inclusion criteria were as follows: (1) Case-control or cohort study evaluating the association between MBOAT7 rs641738 and HCC risk; and (2) reported odds ratios (ORs) and 95% confidence intervals (95%CIs) and/or allele frequencies and/or genotypes. If duplicate research reports were retrieved, the most comprehensive report was selected to avoid repeated statistics. Studies were excluded if they met one of the following criteria: (1) Review, comment, or conference abstract; and (2) insufficient data to estimate OR and 95%CI.

The following data were extracted from each included study: Author, publication year, country, cohort characteristics, sample size, genotype distribution, allele distribution, minor allele frequency, genotyping method, genetic models, adjustment, and Hardy-Weinberg equilibrium (HWE) data. Two authors independently assessed the studies, and disagreements were resolved through discussion with a third author.

Statistical analysis for meta-analysis

We further conducted a meta-analysis using the cohorts of the included studies. We used the HardyWeinberg package (1.7.5) to calculate HWE in the control group of each cohort and performed the meta-analysis using the "metabin", "metagen", and "metainf" functions of the meta package (6.5-0) in R (4.3.0). Between-study heterogeneity was examined using the Q test and quantified using I2. If I2 > 50%, heterogeneity was considered significant, and a random-effects model was applied. Otherwise, a common-effects model was used. Sensitivity analysis was carried out by re-estimating pooled ORs and 95%CIs after excluding each eligible study in turn to assess the stability of the pooled results. Publication bias was evaluated using a funnel plot.

This meta-analysis was performed according to the guidelines of the PRISMA[10]. The meta-analysis was registered in PROSPERO (CRD42023458046).

RESULTS
Systematic review of association of MBOAT7 rs641738 polymorphism with HCC susceptibility

A total of 153 records were found in four different databases; 40 records were found in PubMed, 77 in the Web of Science, 22 in Scopus, and 14 in EMBASE. After removing 55 duplicates and 24 meeting conferences or records without abstracts, we rigorously reviewed the titles and abstracts of the remaining 74 records. We assessed 24 full-text reports for eligibility and included 8 studies in the systematic review (Figure 1).

Figure 1
Open in New Tab   Full Size Figure   Download Figure
Figure 1 Flow diagram for literature search and study selection.

Detailed information on the included studies is shown in Table 1. Our systematic review encompassed a comprehensive analysis of eight studies, spanning from 2016 to 2022, that explored the connection between the MBOAT7 rs641738 polymorphism and HCC. Notably, the majority of these studies (n = 6) were conducted outside of Asia. Of these, one study[8] concentrated solely on HCV-related HCC, while another[11] exclusively addressed alcohol-related HCC. Furthermore, two studies focused on HCC arising from NAFLD[12] or metabolic dysfunction-associated fatty liver disease[13], while another two[9,14] investigated a mixed cohort of NAFLD, viral, and alcohol-related HCC. One study[15] encompassed HCC occurring in the context of compensated cirrhosis (HCV or alcohol), and one[16] did not specify the particular characteristics of the included patient cohort. The genetic analysis techniques employed were diverse, with the TaqMan genotyping method being utilized in most studies (n = 5), with one study employing the MassARRAY[16] and two[12,13] employing United Kingdom Biobank Axiom array methodologies. A subset of studies (n = 4) explicitly delineated the genetic models employed in their analysis. Specifically, two studies[9,11] employed additive models, one[8] adopted a dominant model, and another[16] performed an investigation across dominant, additive, recessive, and allelic models. Conversely, the remaining four studies did not expound upon the genetic models utilized.

Table 1 Systematic review of MBOAT7 rs641738 and hepatocellular carcinoma susceptibility.
Ref.
Country
Cohort characteristics
Study design
Genotyping method
Genetic model(s)
Main results
Conclusion
Thabet et al[8], 2016Multi-countriesHCV-related HCC1706 with chronic HCV infection, divided into two cohorts: Discovery cohort (n = 931) and validation cohort (n = 775)TaqManDominant modelNo significant association was observed with HCC (OR: 0.96; 95%CI: 0.58-1.57)The role of rs641738 is limited to the early stages of liver disease, but not to further progression or occurrence of HCC
Donati et al[9], 2017Multi-countriesNAFLD, HCV, and alcohol-related HCCItalian (n = 765) and United Kingdom (n = 358) NAFLD patients; combined cohort of chronic hepatitis C (n = 597) or alcoholic liver disease (n = 524)TaqManAdditive modelsIn Italian NAFLD patients, the T allele was associated with NAFLD-HCC (OR: 1.65, 95%CI: 1.08-2.55; n = 765). In United Kingdom & Italian NAFLD cohort with non-cirrhotic NAFLD, the T allele remained associated with HCC (OR: 2.10, 95%CI: 1.33-3.31; n = 913). In combined cohort of chronic hepatitis C or alcoholic liver disease, the T allele was independently associated with HCC risk (OR: 1.93, 95%CI: 1.07-3.58; n = 1121)The MBOAT7 rs641738 T allele may predispose to HCC in patients without cirrhosis
Stickel et al[11], 2018Multi-countriesAlcohol-related cirrhotic HCC751 cases with alcohol-related cirrhosis and HCC and 1165 controls with alcohol-related cirrhosis without HCCTaqManAdditive modelsThe risk associated with carriage of MBOAT7 rs641738 was not significant (OR: 1.04, 95%CI: 0.88-1.24)Neither heterozygous nor homozygous carriage of the MBOAT7 rs641738 T allele was associated with HCC risk
Raksayot et al[14], 2019ThailandHBV, HCV, and NBNC-related HCCHealthy controls (n = 105), HBV-related HCC (n = 270), HCV-related HCC (n = 131), and NBNC-related HCC (n = 129)TaqManNAThe genotype distribution and T allele frequencies of MBOAT7 rs641738 were similar between groups (NBNC-HCC vs NBNC-cirrhosis OR: 0.86, 95%CI: 0.51-1.46)The data did not reveal any association between MBOAT7 rs641738 and the development of NBNC-HCC
Wang et al[16], 2021ChinaUnspecified779 HCC cases and 1412 cancer-free controls (controls consist of 678 persistent HBV carriers and 734 spontaneously recovered subjects)MassARRAYDominant, additive, recessive, and allelic modelsThe results suggested no association between MBOAT7-TMC4 rs641738 and HCC risk in most genetic modelsThe work highlights that MBOAT7-TMC4 rs641738 is not associated with the risk of HCC
Bianco et al[12], 2021Multi-countriesNAFLD-related HCCAt-risk individuals (NAFLD cohort, n = 2566 and a replication cohort of 427 German patients with NAFLD). The general population (UKBB cohort, n = 364048). TaqMan & United Kingdom BiLEVE and UKBB Axiom arrayNAIn NAFLD cohort, OR: 1.0, 95%CI: 0.7-1.5; in overall UKBB, OR: 1.3, 95%CI: 0.9-1.8; in non-viral UKBB, OR: 1.3, 95%CI 0.9-1.9Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS and PRS predicted HCC more robustly than single variants
Liu et al[13], 2022United KingdomMAFLD-related HCC160979 participants were diagnosed as having MAFLDUnited Kingdom BiLEVE and UKBB Axiom arrayNAModel 2: Adjusted for gender, age, assessment center, genotyping chip, smoking status, physical activity level, overall health rating, average household income, and alcohol consumption. CT vs CC: OR: 1.16, 95%CI: 0.84-1.62; TT vs CC: OR: 1.36, 95%CI: 0.95-1.95MAFLD is independently associated with an increased risk of both intrahepatic and extrahepatic events. The impact of MAFLD on hepatic health events was amplified by variants in fatty liver disease related genes, among which the genetic variations in PNPLA3, TM6SF2, and MBOAT7 play prominent roles
Nahon et al[15], 2023FrenchCompensated cirrhosis (HCV or alcohol)-related HCCCohort 1 (n = 659): Compensated cirrhosis with HCV sustained virologic response. Cohort 2 (n = 486): Compensated alcohol-related cirrhosisTaqManNAIn HCV-cured cohort, CT/TT vs CC: Subhazard ratio: 1.43, 95%CI: 0.68-3.01; In alcohol cohort, CT/TT vs CC: Subhazard ratio: 1.83, 95%CI: 0.85-3.94 (Fine-Gray regression modelling)A 7-SNP genetic risk score was established, which contains PNPLA3, TM6SF2, HSD17B13, APOE, MBOAT7, and WNT3A-WNT9A variants
HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; NAFLD: Nonalcoholic fatty liver disease; HBV: Hepatitis B virus; NBNC: Non-hepatitis B and non-hepatitis C; MAFLD: Metabolic dysfunction-associated fatty liver disease; PRS: Polygenic risk score; OR: Odds ratio; 95%CI: 95% confidence interval; UKBB: United Kingdom Biobank; SNP: Single-nucleotide polymorphism; NA: Not available.

Overall, the prevailing trend in the majority of studies (n = 7) indicated a lack of significant association between the MBOAT7 rs641738 variant and HCC. Among these, Thabet et al[8] examined a cohort of 1706 patients with chronic HCV infection, suggesting that the role of rs641738 was confined to the early stages of liver disease rather than the progression or emergence of HCC. In contrast, Donati et al[9] conducted an investigation on 765 Italian and 358 United Kingdom NAFLD patients, and they postulated that the MBOAT7 rs641738 T allele might predispose individuals to HCC in the absence of cirrhosis. Notably, they discovered that the T allele was autonomously associated with HCC risk in a combined cohort characterized by chronic HCV infection or alcoholic liver disease. To reconcile these divergent findings, both Stickel et al[11] and Raksayot et al[14] pursued separate inquiries, focusing on alcohol-related and virus-related HCC. Intriguingly, both studies arrived at unanimous negative outcomes. In a similar vein, Wang et al[16] undertook a case-control study with unspecified cohort attributes, and they predominantly identified negative associations across various genetic models. The remaining three[12,13,15] studies adopted the polygenic risk score (PRS) approach, which encompassed key genes such as PNPLA3, TM6SF2, and MBOAT7. Through PRS analysis, these investigations successfully stratified patients into distinct risk levels for HCC. However, they consistently observed that MBOAT7's standalone predictive capability was comparatively weak.

Meta-analysis of association of MBOAT7 rs641738 polymorphism with HCC susceptibility

In the meta-analysis, 12 cohorts from 6 studies were rigorously assessed to elucidate the connection between the MBOAT7 rs641738 polymorphism and HCC. To ensure data quality, we excluded the Italian NAFLD-related and HCV-related HCC cohorts from the study by Donati et al[9] due to HWE P values < 0.05. Additionally, we excluded the alcohol-related HCC cohort from the same study due to limited sample size (n = 12). Employing the "metabin" function, we performed calculations for ORs and 95%CIs, except for the combined Italian and United Kingdom NAFLD-related HCC cohort and the United Kingdom Biobank (nonviral) cohort in the study by Bianco et al[12], in which genotype counts were unspecified. We adopted both dominant and recessive models in the meta-analysis. Cohort characteristics are summarized in Table 2.

Table 2 Studies included in meta-analysis.
Ref.CountryCohort characteristicsCasesControlsGenotype (CC/CT/TT)
Allele (C/T)
Minor allele frequency
AdjustmentHWE of control (P value)
Case
Control
Case
Control
Case
Control
Thabet et al[8], 2016MultiHCV-related HCC75170624/35/16531/822/35383/671884/15280.45 (T)0.45 (T)Age, gender, BMI, and Child-Pugh score0.305
Donati et al[9], 2017ItalianNAFLD-related HCC13263326/69/37213/285/135121/143711/5550.46 (C)0.44 (T)Age, gender, obesity, T2DM, and presence of advanced fibrosis0.036
Donati et al[9], 2017Italian & United KingdomNon-cirrhotic NAFLD-related HCC418725/21/15280/422/17031/51982/7620.38 (C)0.44 (T)NA0.664
Donati et al[9], 2017ItalianHCV-related HCC135841/7/5177/259/1489/17613/5550.35 (C)0.48 (T)Age, gender, and genetic variants0.009
Donati et al[9], 2017ItalianAlcohol-related HCC125121/8/3150/251/11110/14551/4730.42 (C)0.46 (T)Age, gender, and genetic variants0.805
Stickel et al[11], 2018Switzerland, Germany & United KingdomAlcohol-related cirrhotic HCC7511165203/363/185314/583/268769/7331211/11190.49 (T)0.48 (T)Age, gender, BMI, and T2DM0.967
Raksayot et al[14], 2019ThailandHBV-related HCC270105140/114/1666/34/5394/146166/440.27 (T)0.21 (T)NA0.943
Raksayot et al[14], 2019ThailandHCV-related HCC13110571/53/766/34/5195/67166/440.26 (T)0.21 (T)NA0.943
Raksayot et al[14], 2019ThailandNBNC-related HCC (containing NAFLD and alcoholic liver disease)12910568/46/1566/34/5182/76166/440.30 (T)0.21 (T)NA0.943
Wang et al[16], 2021ChinaUnspecified7791405426/295/58800/528/771147/4112128/6820.26 (T)0.24 (T)Age, gender, smoking status, and drinking status0.437
Bianco et al[12], 2021Italian & United KingdomNAFLD-related HCC2262338NANANANANANAAge, gender, BMI, and T2DMNA
Bianco et al[12], 2021United KingdomUKBB (Non-viral)202363,846NANANANANANAAge, gender, BMI, T2DM, ethnicity, array batch, and assessment centerNA
HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; HWE: Hardy-Weinberg equilibrium; NAFLD: Nonalcoholic fatty liver disease; HBV: Hepatitis B virus; T2DM: Type 2 diabetes mellitus; BMI: Body mass index; UKBB: United Kingdom BioBank; NBNC: Non-hepatitis B and non-hepatitis C; NA: Not available.

Intriguingly, our meta-analysis revealed an association between the MBOAT7 rs641738 C > T polymorphism and HCC susceptibility in the dominant model (Figure 2). The pooled OR was 1.14 (95%CI: 1.02-1.26, P = 0.020) in the common-effects model used due to low heterogeneity (I2 = 33%, P = 0.15). Robustness was confirmed in the recessive model (Supplementary Figure 1), with a pooled OR of 1.21 (95%CI: 1.05-1.39, P = 0.008). Influential analysis via the leave-one-out method confirmed the stability of our results (Figure 3). Exclusion of the study by Donati et al[9] significantly reduced heterogeneity (I2 = 0%), and the funnel plot indicated this cohort as a source of heterogeneity (Figure 4). Similar outcomes were observed in the recessive model (Supplementary Figures 2 and 3); after omitting Donati et al[9] or Raksayot et al[14], the heterogeneity was significantly reduced (I2 = 0%), and the P value remained < 0.05 in every situation, indicating the robustness of our results.

Figure 2
Open in New Tab   Full Size Figure   Download Figure
Figure 2 Forest plot of association between MBOAT7 rs641738 and hepatocellular carcinoma risk under the dominant model. OR: Odds ratio; 95%CI: 95% confidence interval; HBV: Hepatitis B virus; HCV: Hepatitis C virus; UKBB: United Kingdom Biobank.
Figure 3
Open in New Tab   Full Size Figure   Download Figure
Figure 3 Forest plot of influence analysis under the dominant model. OR: Odds ratio; 95%CI: 95% confidence interval; HBV: Hepatitis B virus; HCV: Hepatitis C virus; UKBB: United Kingdom Biobank.
Figure 4
Open in New Tab   Full Size Figure   Download Figure
Figure 4 Funnel plot of included studies in meta-analysis under the dominant model. HBV: Hepatitis B virus; HCV: Hepatitis C virus; UKBB: United Kingdom Biobank.

Subgroup analysis considered viral-related and nonviral-related HCC (Figure 5), revealing no significant associations in either the viral (OR: 1.30, 95%CI: 0.98-1.73) or nonviral subgroup (OR: 1.09, 95%CI: 0.93-1.27). Similar trends were observed in the recessive model (Supplementary Figure 4); in the viral subgroup, the OR was 1.09 (95%CI: 0.69-1.73), while in the nonviral subgroup, the OR was 1.14 (95%CI: 0.96-1.34). Studies were categorized into 5 groups by etiology: HCV, alcohol, NAFLD, hepatitis B virus (HBV), and NAFLD plus alcohol (Figure 6). No significant associations were found in the HCV, HBV, alcohol, or NAFLD subgroup. Notably, in the NAFLD plus alcohol subgroup, the OR was 1.37 (95%CI: 1.01-1.86); however, the same phenomenon was not observed with the recessive model (Supplementary Figure 5). Further stratification by the geographical origin of included patients showed a significant association in Asia (OR: 1.20, 95%CI: 1.03-1.39) but not in Europe (Figure 7). In the recessive model, similar results were observed in the Asia subgroup (OR: 1.43, 95%CI: 1.06-1.94, Supplementary Figure 6). This observation underscores the need for more investigation within the Asian population regarding MBOAT7 polymorphisms and HCC susceptibility.

Figure 5
Open in New Tab   Full Size Figure   Download Figure
Figure 5 Forest plot of subgroup analysis under the dominant model (stratification by viral or non-viral related hepatocellular carcinoma). OR: Odds ratio; 95%CI: 95% confidence interval; HBV: Hepatitis B virus; HCV: Hepatitis C virus; UKBB: United Kingdom Biobank.
Figure 6
Open in New Tab   Full Size Figure   Download Figure
Figure 6 Forest plot of subgroup analysis under the dominant model (stratification by detailed etiology). OR: Odds ratio; 95%CI: 95% confidence interval; HBV: Hepatitis B virus; HCV: Hepatitis C virus; UKBB: United Kingdom Biobank.
Figure 7
Open in New Tab   Full Size Figure   Download Figure
Figure 7 Forest plot of subgroup analysis under the dominant model (stratification by geographical origin). OR: Odds ratio; 95%CI: 95% confidence interval; HBV: Hepatitis B virus; HCV: Hepatitis C virus; UKBB: United Kingdom Biobank.
DISCUSSION

In this systematic review and meta-analysis, a total of 2761 HCC cases and 373376 controls were included. Our results suggested that the MBOAT7 rs641738 polymorphism was positively associated with HCC susceptibility in both dominant and recessive models. Our subgroup analysis indicated that the MBOAT7 rs641738 SNP contributes to hepatocarcinogenesis, especially among Asian populations, warranting further exploration of the underlying mechanisms.

The MBOAT7 rs641738 SNP contributes to hepatocarcinogenesis, which is supported by basic scientific evidence. Longo et al[17] generated a full knockout of MBOAT7 in HepG2 cells (human HCC cell line) and observed an imbalance in mitochondrial dynamics, and the silencing of both MBOAT7 and TM6SF2 impaired mitochondrial activity with a shift toward metabolic reprogramming, which led to hepatocarcinogenesis. Moreover, MBOAT7- and TM6SF2-silenced cells exhibited increased cell survival, proliferation, and invasiveness.

Multiple studies have been conducted to investigate the association between the PRS and HCC susceptibility, and most of them reached a positive conclusion. Most studies established PRS models including genes such as PNPLA3, HSD17B13, TM6SF2, MBOAT7, and GCKR. Thrift et al[18] evaluated the association of PRS with HCC in 1644 patients in the United State and found that HCC risk increased by 134% per unit increase in PRS [hazard ratio (HR): 2.30; 95%CI: 1.35-3.92]. Similarly, Degasperi et al[19] included 509 patients with HCV cirrhosis and found that the PRS was an independent predictor of HCC (HR: 2.30, P = 0.04). In contrast, single genetic risk variants were not useful in stratifying HCC risk. Importantly, the PRS method represents a comprehensive assessment of the multiple aspects involved in cancer development. However, the inclusivity of gene sets within the PRS framework remains inconsistent, necessitating further fundamental investigations to refine the approach.

There remain some limitations in this study. First, the included studies in our meta-analysis exhibited diverse etiologies of HCC, which could influence our outcomes. To address this variability, we conducted subgroup analyses and found that the conspicuously positive outcomes might be attributed to studies focused on Asian patients. Additionally, HCC susceptibility could be influenced by patient characteristics, such as age, sex, and smoking habits. Due to the unavailability of the original data of the included studies, this could generate bias in the interpretation of the results. However, the sensitivity analyses confirmed the robustness of our results.

CONCLUSION

In summary, this meta-analysis underscores the contribution of the MBOAT7 rs641738 SNP to hepatocarcinogenesis, especially in Asian populations, which warrants further investigation.

ARTICLE HIGHLIGHTS
Research background

The MBOAT7 rs641738 single-nucleotide polymorphism (SNP) has been proven to influence various liver diseases, but its association with hepatocellular carcinoma (HCC) susceptibility has been debated. To address this discrepancy, we conducted the current systematic review and meta-analysis.

Research motivation

Investigating whether MBOAT7 SNP has an association with HCC susceptibility could help identify at-risk population.

Research objectives

We conducted a systematic review and meta-analysis on the association of the MBOAT7 SNP and HCC susceptibility, aiming to provide an updated and comprehensive assessment of the evolving evidence in this area.

Research methods

We performed a systematic review in PubMed, Web of Science, Scopus, and EMBASE; applied specific inclusion and exclusion criteria; and extracted the data. Meta-analysis was conducted with the meta package in R. Sensitivity and subgroup analyses were also performed.

Research results

Eight studies were included in the systematic review, and 12 cohorts from 6 studies were included in the meta-analysis. Our meta-analysis revealed an association between the MBOAT7 SNP and HCC susceptibility in both the dominant [odds ratio (OR): 1.14, 95% confidence interval (95%CI): 1.02-1.26, P = 0.020] and recessive (OR: 1.21, 95%CI: 1.05-1.39, P = 0.008) models. Subgroup analysis revealed that stratification of the included patients by geographical origin showed a significant association in Asia (OR: 1.20, 95%CI: 1.03-1.39).

Research conclusions

This meta-analysis underscores the contribution of the MBOAT7 rs641738 SNP to hepatocarcinogenesis, especially in Asian populations, which warrants further investigation.

Research perspectives

Future research should focus on what is the specific molecular biological mechanism of MBOAT7 rs641738 SNP leading to HCC and how to prevent it.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Oncology

Country/Territory of origin: China

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B, B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Tsoulfas G, Greece; Yoshioka K, Japan S-Editor: Lin C L-Editor: Wang TQ P-Editor: Zhao S

References
1.  Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, Dicker DJ, Chimed-Orchir O, Dandona R, Dandona L, Fleming T, Forouzanfar MH, Hancock J, Hay RJ, Hunter-Merrill R, Huynh C, Hosgood HD, Johnson CO, Jonas JB, Khubchandani J, Kumar GA, Kutz M, Lan Q, Larson HJ, Liang X, Lim SS, Lopez AD, MacIntyre MF, Marczak L, Marquez N, Mokdad AH, Pinho C, Pourmalek F, Salomon JA, Sanabria JR, Sandar L, Sartorius B, Schwartz SM, Shackelford KA, Shibuya K, Stanaway J, Steiner C, Sun J, Takahashi K, Vollset SE, Vos T, Wagner JA, Wang H, Westerman R, Zeeb H, Zoeckler L, Abd-Allah F, Ahmed MB, Alabed S, Alam NK, Aldhahri SF, Alem G, Alemayohu MA, Ali R, Al-Raddadi R, Amare A, Amoako Y, Artaman A, Asayesh H, Atnafu N, Awasthi A, Saleem HB, Barac A, Bedi N, Bensenor I, Berhane A, Bernabé E, Betsu B, Binagwaho A, Boneya D, Campos-Nonato I, Castañeda-Orjuela C, Catalá-López F, Chiang P, Chibueze C, Chitheer A, Choi JY, Cowie B, Damtew S, das Neves J, Dey S, Dharmaratne S, Dhillon P, Ding E, Driscoll T, Ekwueme D, Endries AY, Farvid M, Farzadfar F, Fernandes J, Fischer F, G/Hiwot TT, Gebru A, Gopalani S, Hailu A, Horino M, Horita N, Husseini A, Huybrechts I, Inoue M, Islami F, Jakovljevic M, James S, Javanbakht M, Jee SH, Kasaeian A, Kedir MS, Khader YS, Khang YH, Kim D, Leigh J, Linn S, Lunevicius R, El Razek HMA, Malekzadeh R, Malta DC, Marcenes W, Markos D, Melaku YA, Meles KG, Mendoza W, Mengiste DT, Meretoja TJ, Miller TR, Mohammad KA, Mohammadi A, Mohammed S, Moradi-Lakeh M, Nagel G, Nand D, Le Nguyen Q, Nolte S, Ogbo FA, Oladimeji KE, Oren E, Pa M, Park EK, Pereira DM, Plass D, Qorbani M, Radfar A, Rafay A, Rahman M, Rana SM, Søreide K, Satpathy M, Sawhney M, Sepanlou SG, Shaikh MA, She J, Shiue I, Shore HR, Shrime MG, So S, Soneji S, Stathopoulou V, Stroumpoulis K, Sufiyan MB, Sykes BL, Tabarés-Seisdedos R, Tadese F, Tedla BA, Tessema GA, Thakur JS, Tran BX, Ukwaja KN, Uzochukwu BSC, Vlassov VV, Weiderpass E, Wubshet Terefe M, Yebyo HG, Yimam HH, Yonemoto N, Younis MZ, Yu C, Zaidi Z, Zaki MES, Zenebe ZM, Murray CJL, Naghavi M. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3:524-548.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2674]  [Cited by in F6Publishing: 2831]  [Article Influence: 404.4]  [Reference Citation Analysis (0)]
2.  El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264-1273.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2183]  [Cited by in F6Publishing: 2404]  [Article Influence: 200.3]  [Reference Citation Analysis (0)]
3.  Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16:589-604.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2184]  [Cited by in F6Publishing: 2511]  [Article Influence: 502.2]  [Reference Citation Analysis (16)]
4.  Fujiwara N, Hoshida Y. Hepatocellular Carcinoma Risk Stratification by Genetic Profiling in Patients with Cirrhosis. Semin Liver Dis. 2019;39:153-162.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 4]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
5.  Singal AG, Manjunath H, Yopp AC, Beg MS, Marrero JA, Gopal P, Waljee AK. The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis. Am J Gastroenterol. 2014;109:325-334.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 239]  [Cited by in F6Publishing: 249]  [Article Influence: 24.9]  [Reference Citation Analysis (0)]
6.  Tang S, Zhang J, Mei TT, Guo HQ, Wei XH, Zhang WY, Liu YL, Liang S, Fan ZP, Ma LX, Lin W, Liu YR, Qiu LX, Yu HB. Association of TM6SF2 rs58542926 T/C gene polymorphism with hepatocellular carcinoma: a meta-analysis. BMC Cancer. 2019;19:1128.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 33]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
7.  Thabet K, Chan HLY, Petta S, Mangia A, Berg T, Boonstra A, Brouwer WP, Abate ML, Wong VW, Nazmy M, Fischer J, Liddle C, George J, Eslam M. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B. Hepatology. 2017;65:1840-1850.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 62]  [Cited by in F6Publishing: 63]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
8.  Thabet K, Asimakopoulos A, Shojaei M, Romero-Gomez M, Mangia A, Irving WL, Berg T, Dore GJ, Grønbæk H, Sheridan D, Abate ML, Bugianesi E, Weltman M, Mollison L, Cheng W, Riordan S, Fischer J, Spengler U, Nattermann J, Wahid A, Rojas A, White R, Douglas MW, McLeod D, Powell E, Liddle C, van der Poorten D, George J, Eslam M; International Liver Disease Genetics Consortium. MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C. Nat Commun. 2016;7:12757.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 87]  [Article Influence: 10.9]  [Reference Citation Analysis (0)]
9.  Donati B, Dongiovanni P, Romeo S, Meroni M, McCain M, Miele L, Petta S, Maier S, Rosso C, De Luca L, Vanni E, Grimaudo S, Romagnoli R, Colli F, Ferri F, Mancina RM, Iruzubieta P, Craxi A, Fracanzani AL, Grieco A, Corradini SG, Aghemo A, Colombo M, Soardo G, Bugianesi E, Reeves H, Anstee QM, Fargion S, Valenti L. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep. 2017;7:4492.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 133]  [Cited by in F6Publishing: 170]  [Article Influence: 24.3]  [Reference Citation Analysis (0)]
10.  Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R, Glanville J, Grimshaw JM, Hróbjartsson A, Lalu MM, Li T, Loder EW, Mayo-Wilson E, McDonald S, McGuinness LA, Stewart LA, Thomas J, Tricco AC, Welch VA, Whiting P, Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32381]  [Cited by in F6Publishing: 29651]  [Article Influence: 9883.7]  [Reference Citation Analysis (0)]
11.  Stickel F, Buch S, Nischalke HD, Weiss KH, Gotthardt D, Fischer J, Rosendahl J, Marot A, Elamly M, Casper M, Lammert F, McQuillin A, Zopf S, Spengler U, Marhenke S, Kirstein MM, Vogel A, Eyer F, von Felden J, Wege H, Buch T, Schafmayer C, Braun F, Deltenre P, Berg T, Morgan MY, Hampe J. Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis. Am J Gastroenterol. 2018;113:1475-1483.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 74]  [Article Influence: 12.3]  [Reference Citation Analysis (0)]
12.  Bianco C, Jamialahmadi O, Pelusi S, Baselli G, Dongiovanni P, Zanoni I, Santoro L, Maier S, Liguori A, Meroni M, Borroni V, D'Ambrosio R, Spagnuolo R, Alisi A, Federico A, Bugianesi E, Petta S, Miele L, Vespasiani-Gentilucci U, Anstee QM, Stickel F, Hampe J, Fischer J, Berg T, Fracanzani AL, Soardo G, Reeves H, Prati D, Romeo S, Valenti L. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores. J Hepatol. 2021;74:775-782.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 183]  [Cited by in F6Publishing: 204]  [Article Influence: 68.0]  [Reference Citation Analysis (0)]
13.  Liu Z, Suo C, Shi O, Lin C, Zhao R, Yuan H, Jin L, Zhang T, Chen X. The Health Impact of MAFLD, a Novel Disease Cluster of NAFLD, Is Amplified by the Integrated Effect of Fatty Liver Disease-Related Genetic Variants. Clin Gastroenterol Hepatol. 2022;20:e855-e875.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 50]  [Article Influence: 25.0]  [Reference Citation Analysis (0)]
14.  Raksayot M, Chuaypen N, Khlaiphuengsin A, Pinjaroen N, Treeprasertsuk S, Poovorawan Y, Tanaka Y, Tangkijvanich P. Independent and additive effects of PNPLA3 and TM6SF2 polymorphisms on the development of non-B, non-C hepatocellular carcinoma. J Gastroenterol. 2019;54:427-436.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
15.  Nahon P, Bamba-Funck J, Layese R, Trépo E, Zucman-Rossi J, Cagnot C, Ganne-Carrié N, Chaffaut C, Guyot E, Ziol M, Sutton A, Audureau E; ANRS CO12 CirVir and CIRRAL groups. Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis. J Hepatol. 2023;78:584-595.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 15]  [Article Influence: 15.0]  [Reference Citation Analysis (0)]
16.  Wang P, Li Y, Li L, Zhong R, Shen N. MBOAT7-TMC4 rs641738 Is Not Associated With the Risk of Hepatocellular Carcinoma or Persistent Hepatitis B Infection. Front Oncol. 2021;11:639438.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 1]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
17.  Longo M, Meroni M, Paolini E, Erconi V, Carli F, Fortunato F, Ronchi D, Piciotti R, Sabatini S, Macchi C, Alisi A, Miele L, Soardo G, Comi GP, Valenti L, Ruscica M, Fracanzani AL, Gastaldelli A, Dongiovanni P. TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models. Cell Mol Gastroenterol Hepatol. 2022;13:759-788.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 47]  [Article Influence: 15.7]  [Reference Citation Analysis (0)]
18.  Thrift AP, Kanwal F, Liu Y, Khaderi S, Singal AG, Marrero JA, Loo N, Asrani SK, Luster M, Al-Sarraj A, Ning J, Tsavachidis S, Gu X, Amos CI, El-Serag HB. Risk stratification for hepatocellular cancer among patients with cirrhosis using a hepatic fat polygenic risk score. PLoS One. 2023;18:e0282309.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 6]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
19.  Degasperi E, Galmozzi E, Pelusi S, D'Ambrosio R, Soffredini R, Borghi M, Perbellini R, Facchetti F, Iavarone M, Sangiovanni A, Valenti L, Lampertico P. Hepatic Fat-Genetic Risk Score Predicts Hepatocellular Carcinoma in Patients With Cirrhotic HCV Treated With DAAs. Hepatology. 2020;72:1912-1923.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 34]  [Article Influence: 8.5]  [Reference Citation Analysis (0)]